Retinal neurodegenerative diseases refer to retinal conditions characterized by progressive neuronal loss. Diabetic retinopathy, age-related macular degeneration, glaucoma and retinitis pigmentosa are considered retinal diseases in which neurodegeneration plays an essential role.
An in depth analysis of these diseases, their critical sites, as well as of possible ways of protection and ways leading to recovery can be extracted from Schmidt et al., “Neurodegenerative Diseases of the Retina and Potential for the Protection and Recovery”, Current Neuropharmacoloqy—2008, Vol. No. 6, pp.: 164-178.
Diabetic retinopathy (DR) is the most common complication of diabetes and remains the leading cause of blindness among working-age individuals in developed countries. Current treatments for DR such as laser photocoagulation, intravitreous injections of corticosteroids or anti-VEGF agents are indicated in too advanced stages of the disease and are associated with significant adverse effects.
Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina. However, there are some data which suggest that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities that occur in DR as can be deduced from Simó et al. on behalf of the European Consortium for Early Treatment of Diabetic Retinopathy (EUROCONDOR). “Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications”, Br. J. Ophthalmol.—2012, vol. 96, pp. 1285-1290.
In the case of DR the neurodegeneration (loss of effective neurons) occurs at the early stages of the disease and produces functional abnormalities such as the loss of both chromatic discrimination and contrast sensitivity. These alterations can be detected by means of electrophysiological studies in diabetic patients even with less than two years of diabetes duration, that is, before microvascular lesions can be detected under ophthalmologic examination. In addition, a delayed multifocal ERG (electroretinography) implicit time (mfERG-IT) predicts the development of early microvascular abnormalities. Furthermore, neuroretinal degeneration initiates and/or activates several metabolic and signaling pathways which will participate in the microangiopathic process, as well as in the disruption of the blood-retinal barrier (a crucial element in the pathogenesis of DR).
The early stages of retinal neurodegenerative diseases or neurodegeneration associated with these pathologies are not currently treated, although they would prevent advanced lesions, such as microcirculatory problems leading to retinal neovascularization. Thus at early stages, in particular of DR, no treatment is applied and the standard follow-up of the patients is conducted.
On the other hand, when the early stages of these retinal neurodegenerative disease, in particular DR, are the therapeutic target, it would be inconceivable to recommend an aggressive treatment such as laser photocoagulation or intravitreous injections. To date, the use of eye drops has not been considered a good route for the administration of drugs addressed to preventing or arresting DR. This is because it is generally assumed that they do not reach the posterior segment of the eye (ie. the vitreous and the retina), as declared in Urtti A et al., “Challenges and obstacles of ocular pharmacokinetics and drug delivery”. Adv. Drug. Deliv. Rev. 2006, vol. 58, pp. 1131-1135. Although there exists a little evidence that compounds administered in the cornea can reach the retina, they represent isolated cases and correspond to compounds of low molecular weight, such as those referred to in Aiello et al., “Targeting Intraocular Neovascularization and Edema—One Drop at a Time”, N. Eng. J Med—2008, vol. 359, pp. 967-969. Aiello et al. show that in two different assays, a pyrrolidin derived compound (named TG100572, 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-I-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenol)) with the capability of acting as an inhibitor of kinases involved in neovascular generation and retinal edema, was able to reach the target in the retina once administered in the form of eye drops. Nonetheless, this small compound cannot be compared to compounds of other nature, such as peptides or proteins with high molecular weights.
Diabetes is a group of chronic diseases characterized by hyperglycemia. To prevent diabetic complications it is essential to reduce hyperglycemia using blood glucose lowering agents. Therefore, any glucose lowering drug could be theoretically beneficial to prevent or arrest diabetic complications, included DR. However, there is a lack of information regarding a direct effect of antidiabetic agents on DR independently of their action in reducing blood glucose levels. By way of example, the glucagon-like peptide 1 agonists known as exenatide (Byeta, Amylin Pharmaceuticals) and liraglutide (Victoza, Novo Nordisk) are used for treating type 2 diabetes by promoting the lowering of blood glucose levels. Moreover, it is known that these agonists give rise to an improvement in the associated diseases of metabolic syndrome such as obesity and high blood pressure. Also the document of patent application WO2007062434 discloses a pharmaceutical composition to be intranasally administered, in which the same glucagon-like peptide 1 (GLP-1) is delivered for treating metabolic syndrome and diabetic complications, including DR.
From the above, therefore, it is known that administration of such glucagon-like peptide 1 agonists also improve or attenuate DR symptoms, since the leading cause or the origin of the disease, in particular the high levels of glucose in blood, is at final instance improved. Nonetheless, these treatments are not deprived of systemic adverse effects. If, moreover, these substances have to reach the retina at therapeutic concentrations, high doses are required thus increasing the adverse effects.
One study showing neuroprotection mediated by GLP-1R activation in an in vivo model is disclosed in Zhang et al., “Intravitreal injection of exendin-4 analogue protects retinal cells in early diabetic rats”, Invest Ophthalmol Vis Sci.—2011, vol. 52(1), pp. 278-85. The authors reported that intravitreal administration of exendin-4 (exenatide) prevented electroretinography (ERG) abnormalities and morphological features related to neurodegeneration in rats with diabetes induced by streptozotocin (STZ). However, the results in the study of Zhang et al. cannot be easily extrapolated to human DR (or to other diseases with retinal neurodegeneration). Firstly, because in the STZ-DM model the interpretation of the results might be hampered by the neurotoxic effect of STZ. Secondly, although GLP-1R expression has been found in retinas from rats it has not been previously reported in human retinas. Finally, and as above mentioned, intravitreous injections are inappropriately invasive in patients with very few if any microvascular abnormalities in fundoscopic examination.
At present, there are no specific treatments for retinal neurodegenerative diseases. In the particular case of DR, this means that there are no specific treatments for the background retinopathy or non-proliferative DR, as well as for protecting the neuroretina from damage (leading to loss of neurons). Therefore, new pharmacological treatments for the early stages of the disease, when neurodegeneration seems to be starting are needed. Early treatment of DR will be effective in reducing the progression to advanced stages needing aggressive therapies such as surgical intervention.